11p15.4

BRW1C,BWR1C,HLDA2,IPL,TSSC3

The PHLDA2 gene is located in a chromosomal region considered an important center for imprinting and localizing tumor suppressor genes. Alterations in the expression of PHLDA2 has been reported in different types of tumors. However, the attribution of its oncogenic or suppressive functions in tumor development is under investigation (Dai et al., 2012; Hsu et al., 2017; Zhao et al., 2018).

Placental and Fetal Development

Several reports in the literature have been shown the role played by PHLDA2 expression in placental development. Salas et al. (2004), using a transgenic model, demonstrated that loss of Phlda2 expression in animals with wild background causes placentomegaly and increased expression of this gene in the placenta causes a significant delay in placental growth. High expression of the PHLDA2 leads to decreased expression of genes associated with lipids production, regulated by spongiophoblasts, causing placental dwarfism and reduction in the accumulation of placental glycogen (Tunster et al., 2016). High expression of PHLDA2 was also significantly associated with decreased birth weight, showing that PHLDA2 can act to decrease body weight by reducing the size and function of the placenta (Apostolidou et al., 2007). The expression of PHLDA2 in the placenta was significantly correlated with decreased femur growth in fetuses between 19 and 34 weeks of gestation and later associated with a lower bone mineral content of the child at the age of four (Lewis et al., 2012).
PHLDA2 expression has been associated with hydatidiform mole disease, in which an increase in PHLDA2 expression was observed in trophoblast cells, possibly due to trisomy of the 11p15.5 chromosomal region (Fisher et al., 2004).
PHLDA2 expression has also been associated with the development of spontaneous abortions, where the increased expression of this gene was observed in placental and fetal samples in the first half of the interrupted pregnancy, showing that this gene may be a possible marker in fetal growth. In vitro studies, with trophoblast cells with overexpression of PHLDA2, showed inhibition of cell growth, migration, and invasion. On the other hand, PHLDA2 reduced expression showed the opposite effect, with an increase in migration and invasion, suggesting the involvement of PHLDA2 in the development of pre-eclampsia due to inhibition of proliferation, migration, and invasion of trophoblastic cells (Jin et al., 2015).

Lung cancer

High expression of PHLDA2 was observed in samples of lung adenocarcinoma compared to adjacent normal tissue. Increased PHLDA2 expression was associated with poor patient survival, suggesting an oncogenic role of PHLDA2 in the development of lung cancer (Hsu e al., 2017). PHLDA2 was also identified as negatively regulated in lung cancer cell lines after inhibiting the EGFR/ ERBB2 pathway. In addition, PHLDA2 expression showed a direct correlation with the expression of p-AKT, suggesting that PHLDA2 may act in the regulation of oncogenic signaling pathways (Wang et al., 2018).

Osteosarcoma

In osteosarcomas, PHLDA2 has been investigated and reported as a possible gene with tumor-suppressive activities. Osteosarcoma samples showed reduced expression of PHLDA2 when compared to adjacent normal tissue and were found to be associated with clinical-pathological data, such as high tumor grade, presence of metastasis, and tumor recurrence (Dai et al., 2012; Wang et al., 2016). PHLDA2 knockdown results in increased cell proliferation and colony formation decreased cell division and apoptosis, and increased tumor growth, which suggests that inactivation of the PHLDA2 protein may contribute to the development and progression of these tumors (Dai et al., 2012). Osteosarcoma cells with PHLDA2 overexpression show increased autophagy and reduced MTOR phosphorylation via SRC/AKT, leading to suppression of tumorigenesis and metastatic phenotype (Zhao et al., 2018). Recently, negative regulation of PHLDA2 expression has been associated with MIR214 expression, promoting resistance to radiotherapy, pulmonary metastasis, and activation of the AKT pathway, suggesting that PHLDA2/AKT may be a new radiotherapy target in osteosarcomas (Yi Li, et al. 2019).

Pancreatic adenocarcinoma

Pancreatic adenocarcinoma is one of the most lethal cancers, in which only 5% of patients have recurrence-free survival in 5 years. Low expression of PHLDA2, directly modulated by MIR148A-5p, inhibits proliferation, migration, and invasion and increases apoptosis in PANC-1 cells, which are derived from pancreatic carcinoma (Idich et al., 2018).

Colorectal cancer

A recent study found that colorectal tumors showed higher expression of PHLDA2 (transcripts and proteins) when compared to adjacent normal tissues. The inactivation of these proteins in colorectal cancer-derived lineage promoted inhibition of cell growth, migration and invasion, and reduced expression of proteins related to the epithelium-mesenchymal transition, and induction of autophagy through the PI3K/AKT signaling pathway, suggesting that PHLDA2 may play a role in the development and progression of colorectal cancer (Zhan Ma et al., 2020).

Breast cancer

There are few studies in the literature addressing the expression of PHLDA2 in breast cancer. Moon et al. (2015), using patient-derived xenograft (PDX) technique, sought to investigate the prognostic role and a gene signature in breast tumors of the triple-negative subtype. PHLDA2 was shown to be positively regulated in cells of the triple negative breast cancer subtype, and its silencing led to a reduction in invasion and proliferation of MDA-MB-231 cells, suggesting the involvement of PHLDA2 in the breast cancer.